tbuckley/cabot-search huggingface dataset:
Abstract 1755: ADAR1-mediated RNA editing of SCD1 links lipid metabolism to gastric cancer drug resistance and self-renewal
Authors: Jia Jian Loh, Tin Lok Wong, Shixun Lu, Helen HN Yan, Hoi Cheong Siu, Ren Xi, Dessy Chan, Max JF Kam, Lei Zhou, Man Tong, John A. Copland, Leilei Chen, Jingping Yun, Suet Yi Leung, Stephanie Ma
Journal: Cancer Research (2023)

Abstract Targetable drivers governing to 5-fluorouracil and cisplatin (5FU+CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Accordingly, we established 5FU+CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 was demonstrated to confer chemoresistance and self-renewal in an RNA editing-dependent manner. WES-seq coupled with RNA-seq identified enrichment of hyperedited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3’UTR of stearoyl-CoA desaturase (SCD1) increased binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogated chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveiled a novel actionable target to circumvent chemoresistance. Citation Format: Jia Jian Loh, Tin Lok Wong, Shixun Lu, Helen HN Yan, Hoi Cheong Siu, Ren Xi, Dessy Chan, Max JF Kam, Lei Zhou, Man Tong, John A. Copland, Leilei Chen, Jingping Yun, Suet Yi Leung, Stephanie Ma. ADAR1-mediated RNA editing of SCD1 links lipid metabolism to gastric cancer drug resistance and self-renewal [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1755.
Abstract 6608: High-sensitivity detection of specific ultra low-frequency somatic mutations for minimal residual disease monitoring
Authors: Tong Liu, Michael Bocek, Patrick Cherry, Shawn Gorda, Jean Challacombe, Derek Murphy, Esteban Toro
Journal: Cancer Research (2023)

Abstract Minimal/Molecular residual disease (MRD) refers to the small number of tumor cells which may remain within a patient after therapeutic intervention. The detection of these remnants and monitoring of their abundance is a promising prognostic marker to identify individuals at risk of recurrence or in need of adjuvant therapy. Due to the low abundance of ctDNA present in samples obtained during remission, MRD assays need to be highly sensitive. In addition, each individual will have a different set of somatic variants, requiring personalized solutions for detection. Therefore, personalized NGS assays with high sensitivity and specificity are needed for MRD diagnostics. To address this need and empower accurate assessments of MRD, Twist Bioscience has developed the MRD Rapid 500 Panels. This product enables customers to design, manufacture and ship fully personalized MRD panels (up to 500 targets) in as little as six days. To demonstrate the detection sensitivity of Twist Rapid 500 MRD panels, we designed five custom MRD panels which specifically target somatic variants found in Breast, Lung, CRC, Melanoma and Renal Cell Carcinoma. Each of these MRD panels were designed to include 197 targets, with 3-5 variants per tissue origin and a selection of passenger mutations. To create the sample set, we blended synthetic variant sequences with fragmented cell line gDNA (NA12878) to form a contrived specimen which approximates the profile cell-free and circulating tumor DNA. Five frequency levels were created with average VAFs of 0% (WT), 0.01%, 0.05%, 0.1% and 2%. Libraries were prepared with UMI adapters and target enrichment was performed using the MRD panels. With a sequencing depth of 80,000x, variant calling results revealed that an average of 20 SNV targets can be detected with confidence in the 0.01% VAF samples for each MRD panel, clearly distinguishable from the WT control samples. In addition to demonstrating the accuracy of variant calling, we showcase the utility of targeting a large number of variants for the detection of an MRD signature at very low levels (e.g. 0.01% VAF). In summary, the performance of the Twist MRD Rapid 500 Panels showed high detection sensitivity of ultra low-frequency somatic mutations while maintaining high specificity for the purposes of MRD monitoring. *For Research Use Only. Not for use in diagnostic procedures. Citation Format: Tong Liu, Michael Bocek, Patrick Cherry, Shawn Gorda, Jean Challacombe, Derek Murphy, Esteban Toro. High-sensitivity detection of specific ultra low-frequency somatic mutations for minimal residual disease monitoring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6608.
Abstract 5474: Combined use of MRI and TAM analysis in GB monitoring
Authors: Carolina Giordano, Giuseppe Maria Della Pepa, Simona Romano, Laura Marrone, Carlo Maria Donzelli, Maria Fiammetta Romano, Simona Gaudino
Journal: Cancer Research (2023)

Abstract Glioblastoma (GB) is the most frequent and aggressive primary brain tumor. It is a highly infiltrating tumor. Complete eradication by surgery is difficult. The probability of survival beyond two years is very low. Magnetic resonance imaging (MRI) is a routine procedure for diagnosing gliomas. However, morphological MRI often fails to identify and quantify the presence of infiltration in peritumoral non-enhanced areas, resulting in inaccuracy in the assessment of invasive margins. Up to 50% of the patients show pseudo-progression. Morphological MRI fails to distinguish the marked enhancement in the tumor bed caused by radionecrosis from actual tumor progression. Diagnosis of GB recurrence through MR morphological sequences has a sensitivity and specificity of about 68% and 77%. Such percentages rise thanks to the use of non-morphological sequences (PWI, DWI, MRS), which are used in routine tumor protocols only in large centers and interpreted by expert neuroradiologists. Biomarkers in conjunction with MRI may help improve the classification, prognosis, and treatment choice. GB is highly infiltrated with monocytic cells, tumor-associated macrophages (TAMs), that invade the peripheral blood. Our group has recently identified a splice isoform of FK506-binding protein 51 (FKBP51) as a reliable TAM marker. We found an expansion in circulating CD163/FKBP51s monocytes in a cohort of GB patients. In patients with an MRI diagnosis of complete surgical tumor removal, these monocytes dramatically decreased. In patients with an MRI diagnosis of residual tumor, most of the peripheral CD163 monocytes that in the preoperative stage were FKBP51s- had turned into FKBP51s+. CD163/FKBP51s+ monocytes helped to distinguish between radionecrosis and actual tumor progression. These results suggest that circulating CD163/FKBP51s+ monocytes are associated with GB and can be helpful in monitoring GB patients. Citation Format: Carolina Giordano, Giuseppe Maria Della Pepa, Simona Romano, Laura Marrone, Carlo Maria Donzelli, Maria Fiammetta Romano, Simona Gaudino. Combined use of MRI and TAM analysis in GB monitoring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5474.
Abstract 5941: Sequencing of targeted- and immune-therapy: delineating time dependent changes in both melanoma cells and the immune microenvironment
Authors: Riyaben Patel, Anna Trigos, Nicole Haynes, Emily Lelliott, Grant McArthur, Karen E. Sheppard
Journal: Cancer Research (2023)

Abstract Targeted and immune therapies have transformed outcomes for melanoma patients, nevertheless, significant challenges remain to maximize their clinical benefit. BRAF/MEK targeted therapy (TT) is associated with very high initial response rates that are typically short-lived, while in contrast Immune Checkpoint Inhibitors (ICI) provide more durable responses but have lower initial response rates. Hence, it has been proposed that sequencing ICIs with TT would lead to a higher frequency of durable responses. However, there are many unanswered questions regarding the choice of immunotherapy, the best sequencing strategy and the mechanism leading to this synergy. To address these questions, we have optimized a syngeneic mouse melanoma model, YUMMER1.7-PV1 that is sensitive to both TT and ICIs. Importantly, this model recapitulates the known three therapeutic response phases of targeted therapies: initial response, followed by drug tolerance and then resistance. Investigation of the tumor immune microenvironment (TIME) at these three drug-induced phases, demonstrates that the immune suppressive microenvironment present during the acquired resistant phase is primed at the drug tolerance phase. Utilizing this model, we have explored the time-dependent therapy-induced changes in both tumor cells and the TIME during various TT and ICI sequencing strategies. This information will determine the optimal sequencing strategy of targeted therapy and immunotherapy that will deliver better outcomes for melanoma patients. Citation Format: Riyaben Patel, Anna Trigos, Nicole Haynes, Emily Lelliott, Grant McArthur, Karen E. Sheppard. Sequencing of targeted- and immune-therapy: delineating time dependent changes in both melanoma cells and the immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5941.
Abstract 3497: The polyclonal path to malignant transformation in familial adenomatous polyposis
Authors: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Emma Monte, Si Wu, Casey Hanson, Nasim Bararpour, Stephanie Neves, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K. Guha, Zheng Hu, Rozelle Laquindanum, Meredith A. Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Jeannie Chan, Mathew Ellenberger, Winston R. Becker, Bahareh Bahmani, Basil Michael, Jeanne Shen, Samuel Lancaster, Uri Ladabaum, Anshul Kundaje, Teri A. Longacre, William J. Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis
Journal: Cancer Research (2023)

Abstract Familial adenomatous polyposis (FAP) patients develop hundreds of premalignant polyps that progress to colorectal cancer due to a germline mutation in the APC tumor suppressor. Polyps from FAP patients uniquely facilitate interrogation of the continuum of malignant transformation from histologically normal mucosa to benign and dysplastic polyps and eventual adenocarcinomas. As part of the Human Tumor Atlas Network (HTAN), we performed multi-omic profiling, including whole genome sequencing, on 135 samples from six FAP patients across the pre-malignant continuum spanning all physical regions of the large intestine, and serving as the most comprehensive FAP dataset available. Through a comparative analysis with a published FAP cohort (58 multi-region samples across 5 patients) and sporadic colorectal cancer cohort (n=57), each including benign and malignant samples, we evaluate the timing of driver acquisitions at each stage of malignant progression. Despite being separated by vast regions of histologically normal mucosa, independently evolving polyps show extensive mutation sharing, suggesting FAP polyps are polyclonal in origin. Finally, we leverage a simplified mechanistic model of embryonic colonic development demonstrating that the path to malignant transformation in FAP is consistent with polyclonal origins attributable to early mixing, perhaps as early as in-utero. Taken together, the HTAN FAP Atlas provides a novel window into the earliest stages of cancer formation and may illuminate barriers to malignant transformation and opportunities for earlier intervention. Citation Format: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Emma Monte, Si Wu, Casey Hanson, Nasim Bararpour, Stephanie Neves, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K. Guha, Zheng Hu, Rozelle Laquindanum, Meredith A. Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Jeannie Chan, Mathew Ellenberger, Winston R. Becker, Bahareh Bahmani, Basil Michael, Jeanne Shen, Samuel Lancaster, Uri Ladabaum, Anshul Kundaje, Teri A. Longacre, William J. Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. The polyclonal path to malignant transformation in familial adenomatous polyposis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3497.
Abstract 4946: TOS-358, a first-in-class covalent PI3Kα inhibitor, demonstrates superior efficacy and does not induce significant hyperglycemia at efficacious doses in multiple animal models
Authors: John R. MacDougall, John Bradley, Raymond Mak, Neil Dhawan, Wei Chen
Journal: Cancer Research (2023)

Abstract PI3Kα is frequently mutated in a variety of cancer types, and the PI3K-AKT signaling axis also plays a role in insulin signaling and glucose homeostasis. TOS-358 is a highly selective first-in-class covalent inhibitor of PI3Kα and is currently in clinical development in multiple solid malignancies. Interestingly, TOS-358 potently and specifically inhibits PI3Kα deeply and durably, but does not induce significant hyperglycemia in a variety of animal models. TOS-358 has consistently demonstrated superior efficacy comparing to reversible PI3Kα inhibitors (ATP-competitive and Allosteric) across 30+ different PDX and CDX mutant PI3Kα dependent cancer models. Detailed metabolic studies also revealed TOS-358 does not induce significant hyperglycemia effects in mice, rats and dogs at efficacious doses, which mirrors previous finding that show that PI3Kα knockout does not induce significant hyperglycemia. Furthermore, we elucidate that previous reversible PI3Kα inhibitors lead to dramatic hyperglycemia due to their potent inhibition of multiple PI3K isoforms at effective concentrations of the molecules in a cellular setting. This data reveals that highly specific and potent covalent inhibition of PI3Kα leads to dramatically superior efficacy and an improved safety profile. Citation Format: John R. MacDougall, John Bradley, Raymond Mak, Neil Dhawan, Wei Chen. TOS-358, a first-in-class covalent PI3Kα inhibitor, demonstrates superior efficacy and does not induce significant hyperglycemia at efficacious doses in multiple animal models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4946.
Abstract 3460: Targeting the MIF-CD74 axis to overcome resistance to tyrosine kinase inhibitors in non-small cell lung cancer
Authors: Motohiro Izumi, Meghan Lee, Daisuke Shibahara, Ikei S. Kobayashi, David Plotnick, Susumu S. Kobayashi
Journal: Cancer Research (2023)

Abstract Development of tyrosine kinase inhibitors (TKIs) against oncogenic drivers has significantly improved survival of patients with oncogene-mutated non-small cell lung cancer (NSCLC). However, acquired resistance to TKIs emerges over time in essentially all patients who initially respond. Recent evidence suggests that drug-tolerant persister (DTP) cells, which survive and adapt to targeted therapies during an early phase of treatment, play an important role in the emergence of drug resistance. We previously reported that CD74 expression is upregulated in EGFR-mutated lung cancer after treatment with EGFR-TKIs and that CD74 can be one of the DTP cell markers. However, the mechanism underlying CD74 expression and the role of CD74 in DTP cells remain unclear. Here, we sought to identify the mechanism using cell culture systems and transgenic mouse models. We confirmed that CD74 upregulation at the mRNA level after TKIs treatments in various oncogene-mutated cell lines, including those with EGFR mutations, ROS1 fusions, and ALK fusions. We found that CIITA, upstream of CD74, and TNF-α expression were induced by TKIs treatments in tumor cells, leading to an increase in CD74 expression. In addition, we found that TKIs treatments enhanced the autocrine secretion of macrophage migration inhibitory factor (MIF), a ligand of CD74, from tumor cells, suggesting that autocrine stimulation of the CD74 signaling results in block of apoptosis and emergence of DTP cells. To examine whether CD74 plays an important role in the emergence of resistance to TKIs in vivo, we crossed lung-specific EGFR-L858R-T790M transgenic mice with Cd74 knockout mice. Complete deletion of CD74 overcame or delayed resistance to TKIs. Taken together, the MIF-CD74 axis can be a novel target to overcome resistance in driver-mutated NSCLC. Citation Format: Motohiro Izumi, Meghan Lee, Daisuke Shibahara, Ikei S. Kobayashi, David Plotnick, Susumu S. Kobayashi. Targeting the MIF-CD74 axis to overcome resistance to tyrosine kinase inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3460.
Abstract 3650: STAT1 suppresses KRAS-driven lung adenocarcinoma depending on the tumor microenvironment
Authors: Christoph Trenk, Rebecca Sagmeister, Jaqueline Horvath, Monika Homolya, Andreea Corina Luca, Robert Eferl, Herwig Moll, Emilio Casanova
Journal: Cancer Research (2023)

Abstract Lung cancer is responsible for the majority of cancer-related deaths worldwide. Within this severe disease lung adenocarcinoma (LUAD) belongs to the most common form of lung cancer. LUAD is highly correlated with KRAS mutations. Although, the first KRAS inhibitors entered into clinics recently, therapy resistance arises. Since KRAS-mutant LUAD is an inflammation driven disease, we focus on the JAK-STAT pathway as an alternative target. Preliminary data suggests that human KRAS-mutant LUAD is correlated to enriched JAK-STAT signaling, as well as STAT1 upregulation. Accordingly, we aimed to explore the tumorigenic functions of STAT1 in this form of lung cancer. Genetically engineered C57BL6/N mice which develop autochthonous KRAS-driven and P53-deficient LUAD proficient (KP) and deficient for STAT1 (KPS) were used. In a second mouse model expression of ovalbumin was induced in tumor cells, mimicking a neoantigen to increase immune infiltration in the presence (KPO) or absence of STAT1 (KPOS). Kaplan-Meyer analysis was performed to assess the overall survival. Tumor burden, as well as immune infiltration was analyzed in lungs 6 and 10 weeks after tumor induction via H&amp;E, IHC and IF staining. Furthermore, the lung fluid was collected by bronchoalveolar lavage and used to profile inflammatory cytokines. Deletion of STAT1 reduced the survival in KRAS-driven LUAD mice only when ovalbumin was expressed. Tumor burden and tumor grades were increased in tumors lacking STAT1 at 6 and 10 weeks after tumor initiation. Surprisingly, although tumors of KPOS mice showed a decreased infiltration by T cells and CD4 T cells, CD8 T cell infiltration did not change, suggesting a tumor suppressive function of STAT1 via T cell exhaustion. Moreover, the macrophage attracting cytokine CCL9 secretion was upregulated and the number of tumor infiltrating, immunosuppressive macrophages was increased in KPOS mice. This data implicates a tumor suppressive function of STAT1 by secretion of cytokines that can recruit suppressive myeloid immune cells to the TME leading to CD4 T cell exclusion and CD8 T cell exhaustion. Further studies are needed on the changes in the immune infiltrating cells to explain the mechanism behind these intriguing findings. Citation Format: Christoph Trenk, Rebecca Sagmeister, Jaqueline Horvath, Monika Homolya, Andreea Corina Luca, Robert Eferl, Herwig Moll, Emilio Casanova. STAT1 suppresses KRAS-driven lung adenocarcinoma depending on the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3650.
Abstract 5068: Nintedanib enhances antitumor effects of anti-PD-1 therapies through inhibition of immunosuppressive cells in tumor microenvironment
Authors: Ryo Suzuki, Satoshi Watanabe, Kunihiro Shono, Takaaki Masuda, Tomoki Sekiya, Yuka Goto, Toshiya Fujisaki, Masashi Arita, Aya Ohtsubo, Satoshi Shoji, Tomohiro Tanaka, Koichiro Nozaki, Rie Kondo, Yu Saida, Satoshi Hokari, Riuko Ohashi, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Toshiaki Kikuchi
Journal: Cancer Research (2023)

Abstract Background: Although programmed cell death-1 (PD-1) inhibitors have achieved promising and durable responses in patients with several types of cancer, many patients show intrinsic resistance to PD-1 inhibitors. Extensive studies have demonstrated that immunosuppressive cells are induced in tumor microenvironment and inhibit antitumor effects of PD-1 inhibitors. The aim of current study is to investigate whether nintedanib, which targets multi-tyrosine kinase including vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, reduced immunosuppressive cells in tumor microenvironment and augments antitumor effects of PD-1 inhibitors. Method: Mice were inoculated subcutaneously with CT26 murine colon carcinoma or MC38 murine colon carcinoma and were treated with nintedanib (50 mg/kg), αPD-1mAbs (10 mg/kg) or nintedanib plus αPD-1mAbs. The tumor size was measured in 2 perpendicular dimensions 3 times per week. Types of cells infiltrating into tumors and immune status of tumor-draining lymph nodes were assessed using flow cytometry and immunohistochemistry (IHC). Results: RNA sequencing data revealed that nintedanib decreased gene expression related to endothelial mesenchymal transition, angiogenesis and coagulation. Flow cytometry showed that nintedanib significantly decreased the percentage of myeloid-derived suppressor cells and cancer-associated fibroblast in tumor tissues. Both of flow cytometry and IHC analysis showed that nintedanib significantly increased IFN-ϒ+CD4+ and CD8+ T cells infiltrating in tumors. In addition, nintedanib plus αPD-1mAbs significantly retarded tumor progression. Conclusion: Nintedanib decreased immunosuppressive cells, increased effector T cells, and enhanced anti-tumor effects of αPD-1mAbs. Based on these findings, there are possibility that nintedanib improves clinical outcomes of cancer patients treated with PD-1 inhibitors. Citation Format: Ryo Suzuki, Satoshi Watanabe, Kunihiro Shono, Takaaki Masuda, Tomoki Sekiya, Yuka Goto, Toshiya Fujisaki, Masashi Arita, Aya Ohtsubo, Satoshi Shoji, Tomohiro Tanaka, Koichiro Nozaki, Rie Kondo, Yu Saida, Satoshi Hokari, Riuko Ohashi, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Toshiaki Kikuchi. Nintedanib enhances antitumor effects of anti-PD-1 therapies through inhibition of immunosuppressive cells in tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5068.